Benzothiazepine anti-seizure method

ABSTRACT

Seizures are ameliorated with certain benzothiazepines.

This is a continuation-in-part of PCT/U.S. 89/02220 filed May 23, 1989,which continues Ser. No. 07,198,054 filed May 24, 1988, U.S. Pat. No.4,879,289 (Nov. 7, 1989), incorporated herein by reference.

FIELD

This invention concerns seizure treatment.

BACKGROUND

Zobrist et al., U.S. patent application Ser. No. 70/198,054 filed May24, 1988, U.S. Pat. No. 4,879,289 (Nov. 7, 1989), discloses a method ofameliorating epileptic seizures. That invention in summary is a methodof ameliorating generalized tonic-clonic type epileptic seizures in amammal by systemically administering to a mammal in need of suchtreatment a compound having calcium antagonist activity and the formula:##STR1## wherein X is hydrogen, a lower straight chain or branchedalkyl, hydroxy, a halogen or a lower straight chain or branched alkylhalide; Y is a lower straight chain or branched alkyl; R1 is hydrogen,hydroxy or acetyloxy; R2 and R3 are each a lower straight chain orbranched alkyl or a non-aromatic saturated or unsaturated cycloalkylhaving no more than 6 carbon atoms or together are a heterocuyclic, andpharmaceutically acceptable salts thereof.

The art lacks and needs further methods for ameliorating such seizures.

SUMMARY

This invention provides a method for ameliorating a generalizedtonic-clonic type epileptic seizure in a mammal comprising systemicallyadministering to a mammal in need of treatment therefor aBenzothiazepine-compound in an amount effective to ameliorate saidseizure.

The invention is useful in seizure treatment.

Notably, the present invention provides a further method forameliorating such a siezure as aforesaid. The treatment it provides canbe unexpectedly effective.

Further advantages attend this invention as well.

ILLUSTRATIVE DETAIL

The terms "ameliorating" or "ameliorate" refer herein to improving orimprovement by reduction or termination of the seizure condition of themammal. It refers to all degrees of improvement, also includingprevention.

The term "generalized tonic-clonic type epileptic seizure" refers hereinto the usual or composite form especially denoting a symptom complexcharacteristic of a class or the like of a bilaterally symmetricalconvulsion, without local onset, of a tonoclonic, i.e., of both a tonicand a clonic, nature, which is a state of continuous, unremittingmuscular contraction followed by repetitive contraction and relaxation,i.e., jerking, symptiomatic of a chronic disorder characterized byparoxysmal attacks of brain dysfunction due to excessive neuronaldischarge, and usually associated with some alteration of consciousness.However, as such, the term is intended to represent a diagnosisclassification approved by the International League Against Epilepsy inSeptember of 1981. See e.g., Porter et al., Cleve. Clin. Q., 51 293-305(1984).

The term "systemically administering" refers herein to applying orgiving to the organism entirely as distinguished from any of itsindividual parts. As such, systemically administering of theBenzothiazepine-compound can be generally accomplished by such methodsas, for example, oral ingestion of an oral or sublingual dosage formsuch as a tablet, capsule, bead sample, syrup, elixer, dragee, and soforth and the like, injection of an injectable solution or suspension,application of a transdermal or other external preparation such as asolution, creme, gel or other ointment, and/or insertion of a rapid orsustained release device.

The term "mammal" refers herein to an animal of the class Mammalia. Themammal can be a human being.

The term "need of treatment therefor" refers herein to a conditionrequiring management or relief for the generalized tonic-clonic typeepileptic seizure included are posterior, prophylactic and/or palliativetreatment(s).

The term "Benzothiazepine-compound" refers herein to abenzothiazepine-type compound, and to pharmaceutically acceptablesalt(s) thereof, having calcium antagonist activity and which isrepresented by the following general formula: ##STR2## wherein Q ishydro (H) or halo to include fluoro (F) and chloro (Cl), especially H or8-Cl;

R is H, lower alkoxy, lower haloalkyl, cyano (CN), lower alkyl toinclude methyl (CH3) or halo to include F & Cl, especially H, methoxy(OMe), trifluoromethyl (CF3) or CN;

Y is

OR', wherein R' is H or alkylacyl to include, e.g., lower alkylacyl andadamantylcarboxy, etc., especially H, or lower alkylacyl to includegroups such as acetyl, propionyl, butyryl, pivalyl, valeryl, isovaleryl,etc., provided that then there is full saturation between carbons 2 & 3of the benzothiazepine nucleus and 2,3-dihydro-functionality thereat aswell, or

Cl, provided that then there is ethylenic unsaturation between positions2 & 3 of the enzothiazepine nucleus, and

R" is 2-[di(lower alkyl)amino]ethyl (R"1), 3-[di(loweralkyl)amino]propyl (R"2), 2-(pyrrolidino)ethyl (R"3),3-(pyrrolidino)propyl (R"4), 2-piperidino)ethyl (R"5),3-(piperidino)propyl (R"6), 2-(morpholino)ethyl (R"7),3-(morpholino)propyl (R"8) or (N-pyridinium)alkyl with a suitablecounterion being present (+R"9-X), especially R"1, e.g., with R"1 being2-(dimethylamino)ethyl (R"1a) or with R"1 being2-(diisopropylamino)ethyl (R"1b), or R"3, or R"5, or +R"9-X, e.g., with+R"9-X being 2-(N-pyridinium)ethyl with a bromide and/or chloridecounterion being present (+R"9a-X),

provided that, in the cis-configuration, when Q is H or 8-Cl, R ismethoxy, R' is acetyl, and R" is R"1a, the compound is the levorotaryisomer.

Generally, with respect to the 2,3-dihydro compounds, thecis-configuration, i.e, about positions 2 & 3 of the benzothiazepinenucleus, is or can be present, with some exceptions to this, e.g., asaforesaid and also preferably with the trans-configuration, i.e., aboutpositions 2 & 3 of the benzothiazepine nucleus, being present in thecases of Q being H or 8-Cl, R being methoxy.[.,.]. .Iadd.ortrifluoromethyl, .Iaddend.R' being H, and R"being .Iadd.R"1a or.Iaddend.R"5. Also generally, if the compound has a chiral carbon,racemates or separate optical antipodes may be present in the practiceof this invention, with some exceptions to this, e.g., the levorotaryoptical antipodes corresponding to diltiazem and to d-cis-TA3090 beingtwo such exceptions.

Suitable pharmaceutically acceptable salts generally sulfate, thecitrate, and so forth.

The Benzothiazepine-compounds can be made by reacting a suitableglycidic acid ester with a suitable aminothiophenol to preparecorresponding aminophenylthiopropionic acid ester, then cyclyzing thelater ester or its corresponding free acid, followed by N-alkylation and3-acylation as may be desired. See e.g., Kugita et al., U.S. Pat. No.3,562,257 (Feb. 9, 1971); Takeda et al., U.S. Pat. No. 4,567,175 (Jan.28, 1986); Borcherding et al., U.S. patent application Ser. No.07/440,383 entitled, "BENZOTHIAZEPINES," and filed on even dateherewith; Wynberg et al., Ser. No. 07/195,749, now issued as U.S. Pat.No. 4,885,375 (Dec. 5, 1989); Wynberg et al., U.S. patent applicationSer. No. 07/439,678 entitled, "GLYCIDIC ACID ESTERS BY BAEYER-VILLAGERREARRANGEMENTS," and filed on even date herewith; Martin, U.S. patentapplication Ser. No. 07/440,377 entitled, "CYANO ESTERS AND AZEPINONES,"and filed on even date herewith, and Martin, U.S. patent applicationSer. No. 07/400,658 filed Aug. 31,1989, each of these being incorporatedherein by reference. In addition, the Benzothiazepine-compounds havingthe vinyl chloride at positions 2 & 3 of the benzothiazepine nucleus canbe made by processes known in the art. See e.g., Krapcho et al., U.S.Pat. No. 3,895,006 (Jul. 15, 1975); Krapcho et al., U.S. Pat. No.3,983,106 (Sep. 28, 1976); Krapcho, U.S. Pat. No. 3,075,967 (Jan. 29,1963), each of these being incorporated herein by reference.

The term "an amount effective" refers herein to an effective amount,which is any amount necessary to at least ameliorate, or optimallycompletely control or prevent, the seizures. For example, in humanpatients in general, effective amounts can be about from 0.1 to 300 mgof Benzothiazepine-compound administered per day.

The following further illustrates this invention.

EXAMPLE

All compounds were dissolved in deionized water and administered at adose from 0.1 milligram (mg) per kilogram (kg) of mammal weight to 100to 300 mg per kg of mammal weight. Each sample, or control, wasadministered by interperitoneal injection in a volume of liquid equal to10 microliters (uL) of the liquid per g of mammal weight. Each mammalwas a male CF-1 mouse (Charles Rivers Breeding Laboratories) weighing anaverage of 25 g. One hour after the injection, the mouse was tested. Ingeneral, rotorod toxicity (RT), maximal electroshock seizure (MES) andsubcutaneous pentylenetetraxole seizure threshold (scMET) tests werecarried out, without administration of anesthesia as anesthetic agentsmay have interfered with seizure development and therefore masked anybeneficial actions of the administered compounds, as follows.

The RT test, designed to detect a minimal neurological deficit fromacute compound-induced toxicity in the mouse, required that the mousewas placed on a 1-inch (2.54 cm) diameter knurled plastic rod rotatingat 6 rotations per minute (rpm). Neurological deficit, e.g., ataxia,sedation, hyperexcitability, was indicated by the inability of a mouseto maintain equilibrium on the rotating rod for at least 1 minute ineach of 3 trials, normal mice able to remain indefinitely on therotating rod.

Data from the RT test was used to calculate, by probit analysis, thedose at which 50 percent of mice would fail the RT test. This wasconsidered a toxic dose for half of a sample of mice, i.e., TD50, indose units, i.e., in units of mg per kg.

The MES test, designed to elicit maximal seizure in all normal mice,required that a 60 Hertz (Hz) alternating current (AC) of 50milliamperes (mA), 5 to 7 times that necessary to elicit minimalseizure, was delivered by corneal electrodes for 0.2 seconds. A drop of0.9 weight percent aqueous sodium chloride solution was applied to eacheye of the mouse, and the electrical stimulus was applied. The mouse wasrestrained by hand and released at the time of stimulation in order tovisually observe the entire seizure, which typically lasted forapproximately 22 seconds and was characterized by a short period ofinitial tonic flexion followed by a prolonged period of tonic extension,especially of the hind legs, and finally a short period of terminalclonus. Elimination of the hind-leg tonic-extensor component, i.e.,hind-leg tonic extension that did not exceed a right angle to the trunkof the body, indicated that the compound can prevent MES-induced seizurespread, and therefore, failure of the mouse to extend its hind limbs toan angle with the trunk of the body greater than the right angle wasdefined as protection.

Data from the MES test was used to calculate, by probit analysis, thedose at which 50 percent of mice would be protected in the MES test.This was considered an effective dose for half of a sample of mice,i.e., ED50, in dose units, i.e., in units of mg per kg.

A therapeutic index (TI) can be calculated by dividing the TD50 by theED50. The TI is indicative of a margin of safety of a drug such that thehigher the TI of a drug, the safer it is.

The scMET test, designed to produce threshold or minimal (olonio)seizures, required the subcutaneous administration of METRAZOL, as asolution of 0.85 weight percent METRAZOL in 0.9 weight percent aqueoussodium chloride solution, in a loose fold of skin on the back of theneck of the mouse in a dose of 85 mg per kg. The mouse was observed forseizures for 30 minutes after the METRAZOL administration, during whichtime characteristic clonic seizures are produced in approximately 98percent of normal mice. The absence of a single 5 second episode ofclonic spasms, a threshold seizure, was defined as protection.

Table I identifies compounds tested, with substituent references beingmade to the formula I. Note that the compounds are specificallyidentified in terms of particular isomers or configurations. However,analogous compound nomenclature without such specific identificationrefers to all isomeric homologs of that compound. Table II listsresults, with dose units being mg per kg.

                  TABLE I                                                         ______________________________________                                                                  Y:R' of                                             Compound   Q      R       OR' & C R"    Salt                                  ______________________________________                                        1-cis-DTZ  H      OMe     acetyl  R"1a  HCl                                   1-cis-TA3090                                                                             8-Cl   OMe     acetyl  R"1a  maleate                               d-cis-ML1013                                                                             H      OMe     valeryl R"1a  fumerate                              d-cis-ML1014                                                                             H      OMe     isovaleryl                                                                            R"1a  fumerate                              d-cis-ML1015                                                                             H      OMe     pivalyl R"1a  fumerate                              d-cis-ML1016                                                                             H      OMe     acetyl  R"1b  HCl                                   dl-cis-NL1017                                                                            H      OMe     H       R"5   HCl                                   dl-cis-ML1018                                                                            H      OMe     acetyl  R"5   HCl                                   dl-cis-ML1020                                                                            H      OMe     H       R"3   HCl                                   dl-cis-ML1021                                                                            H      OMe     acetyl  R"3   HCl                                   d-cis-ML1047                                                                             8-Cl   OMe     pivalyl R"1a  fumerate                              dl-cis-ML1048                                                                            H      OMe     H       R"6   HCl                                   dl-cis-ML1063                                                                            H      OMe     H       R"7   HCl                                   dl-cis-ML1064                                                                            H      OMe     acetyl  R"7   HCl                                   dl-cis-ML1065                                                                            H      OMe     H       +R"   Br/Cl                                                                   9a-X                                        dl-cis-ML1066                                                                            H      OMe     acetyl  +R"   Br/Cl                                                                   9a-X                                        dl-cis-ML1077                                                                            H      Cl      H       R"1a  HCl                                   dl-trans-ML1078                                                                          H      CF3     H       R"1a  HCl                                   dl-cis-ML1079                                                                            H      Me      H       R"1a  HCl                                   d-cis-ML1080                                                                             H      OMe     adaman- R"1a  fumerate                                                        tylcarbonyl                                         dl-trans-ML1082                                                                          H      CF3     H       R"5   HCl                                   dl-trans-ML1096                                                                          8-Cl   OMe     H       R"5   HCl                                   ML1097     H      OMe     *Cl     R"1a  HCl                                   dl-cis-ML1098                                                                            H      H       H       R"5   HCl                                   ml-trans-ML1103                                                                          H      OMe     H       R"5   HCl                                   dl-cis-ML1104                                                                            H      CN      H       R"5   HCl                                   ______________________________________                                         *vinyl chloride at position 2, 3                                         

                  TABLE II                                                        ______________________________________                                                  MES protection                                                      Compound  @ Dose      ED50    TD50  TI  scMET                                 ______________________________________                                        1-cis-DTZ 50% (5/10)                    None                                            @ 100                                                               1-cis-TA3090                                                                            40% (2/5)                     None                                            @ 100                                                               d-cis-ML1013                                                                            0% (0/8)                      None                                            @ 100                                                               d-cis-ML1014                                                                            20% (2/10)                    None                                            @ 100                                                               d-cis-ML1015                                                                            0% (0/9)                      None                                            @ 100                                                               d-cis-ML1016                                                                            89% (8/9)                     None                                            @ 100                                                               dl-cis-ML1017                                                                           100% (10/10)                  None                                            @ 100                                                               dl-cis-ML1018                                                                           90% (9/10)  45.6              None                                            @ 100                                                               dl-cis-ML1020                                                                           70% (7/10)                    None                                            @ 100                                                               dl-cis-ML1021                                                                           89% (8/9)   76.1     97.5 1.3 None                                            @ 100                                                               dl-cis-ML1048                                                                           0% (0/9)                      None                                            @ 100                                                               dl-cis-ML1063                                                                           20% (2/10)                    None                                            @ 100                                                               dl-cis-ML1064                                                                           20% (2/10)                    None                                            @ 100                                                               dl-cis-ML1065                                                                           0% (0/8)                      None                                            @ 100                                                               dl-cis-ML1066                                                                           0% (0/4)                      None                                            @ 100                                                               dl-cis-ML1077                                                                           100% (10/10)                                                                              55.7              None                                            @ 100                                                               dl-trans- 100% (10/10)                                                                              13.4     84.5 6.3 None                                  ML1078    @ 100                                                               dl-cis-ML1079                                                                           50% (5/10)                    None                                            @ 100                                                               d-cis-ML1080                                                                            0% (0/5)                      None                                            @ 100                                                               dl-trans- 100% (12/12)                                                                              23.7              None                                  ML1082    @ 100                                                               dl-trans- 30% (3/10)  87.2    203.1 2.3 None                                  ML1096    @ 100                                                               ML1097    90% (9/10)  47.7    125.2 2.6 None                                            @ 100                                                               dl-cis-ML1098                                                                           0% (*0/10)                    None                                            @ 100                                                               dl-trans- 100% (10/10)                  None                                  ML1103    @ 100                                                               dl-cis-ML1104                                                                           20% (1/5)                     None                                            @ 100                                                               ______________________________________                                         *100% death at this dose                                                 

In conjunction with Table II, the following salient data was collectedand is listed as follows. The list employs the following format:Benzothiazepine-compound as identified in Table I: Dose, in mg per kg,test, i.e., RT (number not having observed deficit/number tested, plusany comments) and MES (number protected/number tested, plus anycomments).

d-cis-MLI016 30, RT (0/5) MES (0/5); 60, RT (0/5) MES (1/5); 100, RT(0/4, 1 died) MES (3/4, 1 died),

dl-cis-ML1017: 3, RT (0/10) MES (0/10); 10, RT (0/14) MES (0/14); 30, RT(0/14) MES (0/14); 100, RT (9/9) MES (9/9); 200, (4 tested, and 4 died).

dl-cis-ML1018: 30, RT (0/11) MES (1/11); 60, RT (1/5) MES (4/5); 100, RT(4/4) MES (4/4).

dl-cis-ML1021: 30, RT (0/5) MES (0/5) MES (0/5); 60, RT (0/5) MES (1/5);80, RT (2/5) MES (3/5); 100, RT (2/5) MES (4/5); 120, RT (3/3, 2 died)MES (1/3); 140, RT (1/1, 4 died) MES (1/I, 4 died); 200, RT (1/1, 4died) MES (1/1, 4 died).

dl-cis-ML1048: 10, RT (0/4) MES (0/4); 30, RT (0/4) MES (1/4); 60, RT(1/3) MES (3/3); 100, RT (3/3) MES (3/3).

dl-cis-ML1077: 10, RT (0/4) MES (0/4); 30, RT (0/4) MES (0/4); 40, RT(0/5) MES (0/5); 50, RT (0/5) MES (2/5); 60, RT (I/9) MES (6/9); 80, RT(0/9) MES (9/9); 100, RT (5/19) MES (18/19); 110, RT (2/5) MES (5/5);120, RT (1/5) MES (5/5).

dl-.[.cis.]..Iadd.trans.Iaddend.-ML1078: 3, RT (0/5) MES (0/5); 10, RT(0/9) MES (3/9); 30, RT (1/9) MES (8/9); 60, RT (0/5) MES (5/5); 100, RT(3/9) MES (9/9); 110, RT (4/5) MES (5/5); 120, RT (10/10) MES (10/10);160, RT (5/5) MES (5/5); 200, RT (5/5) MES (5/5).

dl-.[.cis.]..Iadd.trans.Iaddend.-ML1082: 3, RT (0/12) MES (0/12); 10, RT(0/11) MES (2/21); 30, RT (0/11) MES (12/21); 40, RT (0/5) MES (5/5);60, RT (0/5) MES (14/15); 80, RT (5/5) MES (5/5); 100, RT (6/6) MES(15,16).

dl-trans-ML1096: 30, RT (0/10) MES (1/9); 100, RT (0/10) MES (3/10);120, RT (0/5) MES (5/5); 150, RT (0/10) MES (7/10); 200, RT (8/20) MES(20/20); 205, RT (4/5) MES (4/5); 210, RT (4/5) MES (5/5); 220, RT(10/10) MES (10/10); 230, RT (5/5) MES (5/5); 270, RT (5/5) MES (5/5);300, RT (8/8, 2 died) MES (8/8, 2 died).

ML1097: 3, RT (0/10) MES (0/10); 10, RT (0/10) MES (0/10); 30, RT (0/10)MES (0/10); 40, RT (0/5) MES (3/5); 60, RT (0/5) MES (4/5); 80, RT (0/5)MES (5/5); 100, RT (1/10) MES (9/10); 120, RT (3/5) MES (5/5); 150, RT(2/2) MES (2/2); 160, RT (4/5) MES (5/5); 180, RT (5/5) MES (5/5); 200,RT (9/10) MES (9/10).

dl-trans-ML1103: 30, RT (0/5) MES (0/5); 60, RT (0/5) MES (0/5); 100, RT(0/15) MES (13/15); 120, RT (0/5) MES (5/5); 140, RT (2/5) MES (5/5);160, RT (0/1, 4 died) MES (1/1, 4 died); 180, RT (1/2, 3 died) MES (2/2,3died); 200, RT (4/4, 1 died) MES (4/4, 1 died).

CONCLUSION

The present invention is thus provided. Numerous adaptations andmodifications can be effected by those skilled in the art within thespirit of this invention, the scope of which is particularly pointed outby the following distinctly claimed subject matter.

What is claimed is:
 1. A method for ameliorating a generalized tonicclonic type epileptic seizure in a mammal comprising systemicallyadministering to a mammal in need of treatment therefor aBenzothiazepine-compound in an amount effective to ameliorate saidseizure, wherein the Benzothiazepine-compound is a benzothiazepine-typecompound, or a pharmaceutically acceptable salt thereof, having calciumantagonist activity and which is represented by the following generalformula: ##STR3## wherein Q is hydro (H) or halo:R is H, Lower alkoxy,lower haloalkyl, cyano, lower alkyl or halo; Y is OR', wherein R' is Hof alkylacyl, provided that then there is full saturation betweencarbons 2 & 3 of the benzothiazepine nucleus and2,3-dihydro-functionality thereat as well, orCl, provided that thenthere is ethylenic unsaturation between positions 2 & 3 of theebenzothiazepine nucleus, and R" is 2-[di(lower alkyl)amino ]ethyl,3-[di(lower alkyl)amino]propyl, 2-(pyrrolidino)ethyl,3-(pyrrolidino)propyl, 2-(piperidino)ethyl, 3-(piperidino)propyl,2-(morpholino)ethyl, 3-(morpholino)propyl or (N-pyridinium)alkyl with asuitable counterion being present, provided that, in thecis-configuration, when Q is H or 8-Cl, R is methoxy, R' is acetyl, andR" is 2-(dimethylamino)-ethyl, then the compound is the levorotaryisomer.
 2. The method of claim 1, wherein the Benzothiazepine-compoundis selected from the group consisting of 1-cis-DTZ, 1-cis-TA3090,M11014, ML1016, ML1017, ML1018, ML1020, ML1021, ML1048, ML1063, ML1064,ML1077, ML1078, ML1079, ML1082, ML1096, ML1097, ML1103, ML1104, andpharmaceutically acceptable salt(s) thereof, wherein each particularcompound is identified as follows with respect to the formula (I):

    ______________________________________                                                                     Y:R' of                                          Compound    Q        R       OR' & C   R"                                     ______________________________________                                        1-cis-DTZ   H        OMe     acetyl    R"1a                                   1-cis-TA3090                                                                              8-Cl     OMe     acetyl    R"1a                                   ML1014      H        OMe     isovaleryl                                                                              R"1a                                   ML1016      H        OMe     acetyl    R"1b                                   ML1017      H        OMe     H         R"5                                    ML1018      H        OMe     acetyl    R"5                                    ML1020      H        OMe     H         R"5                                    ML1021      H        OMe     acetyl    R"3                                    ML1048      H        OMe     H         R"6                                    ML1063      H        OMe     H         R"7                                    ML1064      H        OMe     acetyl    R"7                                    ML1077      H        Cl      H         R"1a                                   ML1078      H        CF3     H         R"1a                                   ML1079      H        Me      H         R"1a                                   ML1082      H        CF3     H         R"5                                    ML1096      8-Cl     OMe     H         R"5                                    ML1097      H        OMe     *Cl       R"1a                                   ML1103      H        OMe     H         R"5                                    ML1104      H        CN      H         R"5                                    ______________________________________                                    

wherein also with respect to Q, 8-Cl is 8-chloro; with respect to R, OMeis methoxy; Cl is chloro; CF3 is trifluoromethyl; Me is methyl, and CNis cyano; with respect to Y, *CI indicates vinyl chloride at position 2,3 of the benzothiazepine nucleus, and with respect to R", R"1a is2-(dimethylamino)ethyl; R"1b is 2-(diisopropylamino)ethyl; R"3 is2-(pyrrolidino)ethyl; R"5 is 2-(piperidino)ethyl; R"6 is3-(piperidino)propyl, and R"7 is 2-(morpholino)ethyl.
 3. The method ofclaim 2, wherein the Benzothiazepine-compound is selected from the groupconsisting of ML11016, ML1017, ML1018, ML1021, ML1048, ML1077, ML1078,ML1103, and pharmaceutically acceptable salt(s) thereof.
 4. The methodof claim 2, wherein the Benzothiazephine-compound is selected from thegroup consisting of ML1021, ML1077, ML11078, ML1082, ML1096, andpharmaceutically acceptable salt(s) thereof.
 5. The method of claim 2,wherein the Benzothiazephine-compound is selected from the groupconsisting of d-cis-ML1014, d-cis-ML1016, cis-ML1017, cis-ML1018,cis-ML1020, cis-MLI1021, cis-ML1048, cis-ML1063, cis-ML1064, cis-ML1077,.[.cis.]. .Iadd.trans.Iaddend.-ML1078, cis-ML1079, .[.cis.]..Iadd.trans.Iaddend.-ML1082, trans-ML1096, trans-ML1103, cis-ML1104, andpharmaceutically acceptable salt(s) thereof.
 6. The method of claim 2,wherein the Benzothiazephine-compound is selected from the groupconsisting of cis-ML1016, cis-ML1017, cis-ML1018, cis-ML1021,cis-ML1048, cis-ML1077, .[.cis.]. .Iadd.trans.Iaddend.-ML1078,trans-ML1103, and pharmaceutically acceptable salt(s) thereof.
 7. Themethod of claim 2, wherein the Benzothiazephine-compound is selectedfrom the group consisting of cis-ML1077, .[.cis.]..Iadd.trans.Iaddend.-ML1078, .[.cis.]. .Iadd.trans.Iaddend.-ML1082,trans-ML1096, and pharmaceutically acceptable salt(s) thereof.
 8. Themethod of claim 7, wherein the pharmaceutically acceptable salt is ahydrochloride salt.
 9. The method of claim 2, wherein theBenzothiazephine-compound is 1-cis-TA3090, or a pharmaceuticallyacceptable salt thereof.
 10. The method of claim 9, wherein thepharmaceutically acceptable salt is a maleate salt.
 11. The method ofclaim 2, wherein the Benzothiazephine-compound is 1-cis-DTZ, or apharmaceutically acceptable salt thereof.
 12. The method of claim 11,wherein the pharmaceutically acceptable salt is a hydrochloride salt.13. The method of claim 2, wherein the Benzothiazepine-compound isML1097, or a pharmaceutically acceptable salt thereof.
 14. The method ofclaim 13, wherein the pharmaceutically acceptable salt is ahydrochloride salt.
 15. The method of claim 1, wherein theBenzothiazepine-compound is selected from the group consisting of thefollowing salts, identified as follows with respect to the formula (I):

    ______________________________________                                                                  Y:R' of                                             Compound   Q      R       OR' & C R"    Salt                                  ______________________________________                                        1-cis-DTZ  H      OMe     acetyl  R"1a  HCl                                   1-cis-TA3090                                                                             8-Cl   OMe     acetyl  R"1a  maleate                               d-cis-ML1013                                                                             H      OMe     valeryl R"1a  fumerate                              d-cis-ML1014                                                                             H      OMe     isovaleryl                                                                            R"1a  fumerate                              d-cis-ML1015                                                                             H      OMe     pivalyl R"1a  fumerate                              d-cis-ML1016                                                                             H      OMe     acetyl  R"1b  HCl                                   dl-cis-ML1017                                                                            H      OMe     H       R"5   HCl                                   dl-cis-ML1018                                                                            H      OMe     acetyl  R"5   HCl                                   dl-cis-ML1020                                                                            H      OMe     H       R"3   HCl                                   dl-cis-ML1021                                                                            H      OMe     acetyl  R"3   HCl                                   d-cis-ML1047                                                                             8-Cl   OMe     pivalyl R"1a  fumerate                              dl-cis-ML1048                                                                            H      OMe     H       R"6   HCl                                   dl-cis-ML1063                                                                            H      OMe     H       R"7   HCl                                   dl-cis-ML1064                                                                            H      OMe     acetyl  R"7   HCl                                   dl-cis-ML1065                                                                            H      OMe     H       +R"   Br/Cl                                                                   9a-X                                        dl-cis-ML1066                                                                            H      OMe     acetyl  +R"   Br/Cl                                                                   9a-X                                        dl-cis-ML1077                                                                            H      Cl      H       R"1a  HCl                                   dl-trans-ML1078                                                                          H      CF3     H       R"1a  HCl                                   dl-cis-ML1079                                                                            H      Me      H       R"1a  HCl                                   d-cis-ML1080                                                                             H      OMe     adaman- R"1a  fumerate                                                        tylcarboxy                                          dl-cis-ML1082                                                                            H      CF3     H       R"5   HCl                                   dl-trans-ML1096                                                                          8-Cl   OMe     H       R"5   HCl                                   ML1097     H      OMe     *Cl     R"1a  HCL                                   dl-cis-ML1098                                                                            H      H       H       R"5   HCl                                   dl-trans-ML1103                                                                          H      OMe     H       R"5   HCl                                   dl-cis-ML1104                                                                            H      CN      H       R"5   HCl                                   ______________________________________                                    

wherein also with respect to Q, 8-Cl is 8-chloro; with respect to R, OMeis methoxy; Cl is chloro; CF3 is trifluoromethyl; Me is methyl, and CNis cyano; with respect to Y, *Cl indicates vinyl chloride at position2,3 of the benzothiazepine nucleus, and with respect to R", R"1a is2-(dimethylamino)ethyl; R"1b is 2-(diisopropylamino)ethyl: R"3 is2-(pyrrolidino)ethyl; R"5 is 2-(piperidino)ethyl; R"6 is3-(piperidino)propyl; R"7 is 2-(morpholino)ethyl, and +R"9a-X is2-(N-pyridinium)ethyl with a bromide and/or chloride counterion beingpresent.